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J. Biol. Chem., Vol. 283, Issue 23, 15988-15996, June 6, 2008

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The Same Primary Structure of the Prion Protein Yields Two Distinct Self-propagating States^*

From the Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, Maryland 21201

The question of whether distinct self-propagating structures could be formed within the same amino acid sequence in the absence of external cofactors or templates has important implications for a number of issues, including the origin of prion strains and the engineering of smart, self-assembling peptide-based biomaterials. In the current study, we showed that chemically identical prion protein can give rise to conformationally distinct, self-propagating amyloid structures in the absence of cellular cofactors, post-translational modification, or PrP^Sc-specified templates. Even more surprising, two self-replicating states were produced under identical solvent conditions, but under different shaking modes. Individual prion conformations were inherited by daughter fibrils in seeding experiments conducted under alternative shaking modes, illustrating the high fidelity of fibrillation reactions. Our study showed that the ability to acquire conformationally different self-propagating structures is an intrinsic ability of protein fibrillation and strongly supports the hypothesis that conformational variation in self-propagating protein states underlies prion strain diversity.

Received for publication, January 23, 2008 , and in revised form, April 3, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant NSO45585 (to I. V. B.). This work was also supported by the Program in Prion Diseases at the Medical Biotechnology Center, UMBI. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ To whom correspondence should be addressed: Medical Biotechnology Center, University of Maryland Biotechnology Inst., 725 W. Lombard St., Baltimore, MD 21201. Tel.: 410-706-4562; Fax: 410-706-8184; E-mail: Baskakov{at}umbi.umd.edu.

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